ThefocusofProject1onBioenergeticandMetabolicConsequencesoftheLossofGonadalFunctionin WomenintheColoradoSCORE(CO-SCORE)isbasedontheoverarchinghypothesisthatthelossofgonadal functionincreasesriskforchronicdisease.Thebest-studiedexampleofthisistheaccelerateddeclineinbone mineraldensityatmenopauseandtheresultingriskforosteoporosis.However,theextenttowhichgonadal agingincreasesriskforchronicdiseasesotherthanosteoporosisispoorlyunderstood.Thisisparticularly relevanttowomen?shealth,becausegonadalfailureisinevitableinwomeninmid-lifebutrareinmenuntil muchlaterinlife.DuringthecurrentSCOREawardperiod,weadvancedtheclinicaltranslationofthe unequivocalevidenceinanimalsthatlossofestradiol(E2)isatriggerforexcessabdominalfataccumulation andmetabolicdysfunction.Wedemonstratedthatsuppressionofovarianfunctioninpremenopausalwomen (gonadotropinreleasinghormoneagonist;?GnRHAG)disruptsenergyhomeostasis,andresultsinamarked increaseinabdominalsubcutaneousandvisceralfatthatispreventedbyE2add-back.Wealsogenerated intriguingpreliminarydatatosupportthehypothesisthattheconversionofcortisonetocortisolinabdominal adiposetissuebytheenzyme11?-hydroxysteroiddehydrogenase1(HSD1)isregulatedbyE2.Preclinical evidencestronglysupportsglucocorticoidmetabolismasaregulatorofabdominaladiposity.Accordingly,Aim 1inthenextawardperiodistodeterminewhetheradiposetissueandsystemicglucocorticoid metabolismareregulatedbyE2inwomen.BecauseagoaloftheCO-SCOREistoadvanceparadigm- challengingresearchonsexdifferences,Aim2willinvestigatefolliclestimulatinghormone(FSH)asa mediatorofenergyhomeostasisandcardiometabolicfunction.FSHwasimplicatedrecentlyasa mediatorofmetabolicactionstraditionallyattributedtothelossofE2.Whencomparedwithcontrols,mice treatedwithanFSHantibodyhadincreasedbonemassanddecreasedadiposity,includingreductionsin visceralandsubcutaneousfat.GiventheimportanceofunderstandingwhetherbothE2andFSHmaybe importanttherapeutictargets,ratherthanjustE2,wewillconductthefirstproof-of-conceptstudyofthe effectsofE2vsFSHonoutcomesthatareresponsivetotheinhibitionofFSHinmice.Projects1,2 (preclinical),and3(basic)willalladdressgapsinknowledgeonwhethertheeffectsofE2-deficiencyto increaseabdominaladiposityaremediatedbyalteredglucocorticoidmetabolismand/orincreasedFSH. AdiposetissuesamplesfromwomeninProject1andfromanimalsinProjects2and3willbeinterrogated usingsimilarapproachestoacceleratethetranslationalrelevanceoftheseareasofresearch.Finally,because bloodandtissuesamplesfromexperimentsinwhichwecontrolE2statusareofgreatvalueacrossmany disciplines,wewillbankspecimensfromwomeninProject1thatcanbeusedtosupportexternal collaborationswithSCORE(andother)investigatorsacrossthecountry.